Title: PharmaNote
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Permanent Link: http://ufdc.ufl.edu/UF00087345/00009
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Title: PharmaNote
Series Title: PharmaNote
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Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: March 2003
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Bibliographic ID: UF00087345
Volume ID: VID00009
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Eun-Jeong Kim, Pharm.D. Candidate

Approximately 50 million adult Americans
have high blood pressure. Of those, 73 percent are
not adequately controlled, and are at increased risk
of heart attack, stroke, kidney failure, ocular dam-
age, heart failure, and atherosclerosis.1 Control of
hypertension remains inadequate in many patients
despite the availability of several classes of anti-
hypertensives, such as, angiotensin converting en-
zyme (ACE) inhibitors, P-blockers, calcium chan-
nel blockers (CCB), angiotensin receptor blockers
(ARBs), and diuretics. The high prevalence of hy-
pertension and its link to cardiovascular and renal
disease imposes a large economic burden. It is esti-
mated that hypertension-related morbidity and mor-
tality cost the United States over $34.3 billion in
healthcare expenditures and an additional $12.8 bil-
lion in loss of productivity in 2002.2
Aldosterone, an effector hormone of the
renin-angiotensin-aldosterone system (RAAS),
plays a critical role in the development and pro-
gression of cardiovascular disease.3 Aldosterone
has been linked to hypertension, cardiac hypertro-
phy, cardiac and vascular fibrosis, and ventricular
arrhythmias.47 Recent studies demonstrate that, al-
though the level of aldosterone is suppressed in pa-
tients treated with an angiotensin-converting en-
zyme (ACE) inhibitor or an angiotensin II receptor

blocker (ARB), suppression does not continue with
chronic use of these medications.8-9 Spironolactone,
an aldosterone receptor antagonist, has traditionally
been used as a potassium- and magnesium-sparing
diuretic in the treatment of hypertension and con-
gestive heart failure or in the management of pri-
mary aldosteronism. Although the clinical impor-
tance of aldosterone receptor antagonists in the
treatment of congestive heart failure and hyperten-
sion has been demonstrated with spironolactone, its
use has been limited by progestational and antian-
drogenic side effects including gynecomastia.10
Eplerenone (Inspra) is a new selective al-
dosterone blocker approved by the FDA in October
2002. It is marketed by Pharmacia and is expected
to be released during the first quarter of 2003. In
contrast to spironolactone, eplerenone demonstrates
a high degree of selectivity for the aldosterone re-
ceptor with a low-binding affinity for progesterone
(<1%) and androgen receptors (0.1%).29 This arti-
cle will examine the safety, efficacy, and tolerabil-
ity of eplerenone.

Pharmacology and Pharmacokinetics
Aldosterone synthesis, which occurs pri-
marily in the adrenal gland, is modulated by multi-
ple factors, including angiotensin II and non-RAAS
mediators such as adrenocorticotropic hormone
(ACTH) and potassium. Aldosterone binds to min-
eralocorticoid receptors in both epithelial and non-
epithelial tissues and increases blood pressure
through induction of sodium reabsorption and pos-
sibly other mechanisms. Eplerenone binds to min-
eralocorticoid receptors and blocks the binding of
aldosterone, a component of the RAAS. Eplerenone
produces a sustained increase in plasma renin and
serum aldosterone, consistent with inhibition of the
negative regulatory feedback of aldosterone on

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Table 1. Dose Ranging Studies of Eplerenone 13-14

Study group Demographics Design Dose N Mean A BP (mmHg) SBP/DBP
50 mg/d 68 -15.9/-10.6
Burgess et al.13 Mild to moderate OL, 6 to 16 months mg/d 68
hypertension Titration to effect 100 mg/d 98 -18.1/-12.2
Second medication- 200 mg/d 104 -19.1/-12.5
could be added 200 mg/d 172 -24.9/-14.6
A Clinic BP A Ambulatory BP
(mmHg) (mmHg)
Placebo 90 -0.0/-1.7 -1.3/0.8
White et al.14 Mild to severe 12 weeks 25 mg/d 45 -5.7*/-3.7 -6.4*/-4.4*
hypertension DB, PC, FD 50 mg/d 87 -6.7*/-4.6* -6.8"/-4.1"
Clinic and ambulatory
Cliniandambulatory 100 mg/d 90 -10.4*/-6.3* -9.1*/-5.5*
BP monitoring
200 mg/d 88 -8.8*/-5.4* -10.3*/-5.7*
DBP = diastolic blood pressure, SBP = systolic blood pressure, OL = open label, DB = double-blinded, PC = placebo=controlled, FD = fixed-dose
p < 0.01 for eplerenone vs. placebo

renin secretion. The resulting increased plasma
renin activity and aldosterone circulating levels do
not negate the effect of eplerenone on blood pres-
Eplerenone's mean peak plasma concentra-
tion (Cmax) is reached approximately 1.5 hours fol-
lowing oral administration. Absorption is not af-
fected by food. The absolute bioavailability of
eplerenone is unknown. It is approximately 50%
bound to plasma proteins, primarily a-i-acid glyco-
protein. Eplerenone's metabolism is primarily me-
diated via CYP 3A4 and no active metabolites have
been identified in human plasma to date. Less than
5% of an eplerenone dose is recovered as un-
changed drug in the urine and feces. Following a
single oral dose of radiolabeled drug, approxi-
mately 32% of the dose was excreted in the feces
and approximately 67% was excreted in the urine.
The elimination half life of eplerenone is approxi-
mately 4 to 6 hours. The apparent plasma clearance
is approximately 10 L/hr. Inhibitors of CYP 3A4
(e.g. ketoconazole, saquinavir) increase blood lev-
els of eplerenone. Area under the curve (AUC) and
Cmax were increased by 38% and 24%, respectively,
in patients with severe renal impairment and were
decreased by 26% and 3% respectively, in patients
undergoing hemodialysis when compared with con-
trol subjects. The pharmacokinetics of eplerenone
did not differ significantly between males and fe-
males. However, steady state concentrations of
eplerenone appeared to be higher in the elderly and
lower in African American subjects. 11

Clinical Trials

Numerous studies have investigated
eplerenone's efficacy in different stages of hyper-
tension. These include: dosing-ranging studies,13-14
comparison with other antihypertensive monothera-
pies,15,24,27 and comparisons with other antihyper-
tensive drugs alone or in combination.25-26

Dosing-ranging studies
Two double-blinded, placebo-controlled tri-
als evaluated eplerenone's effect on blood pressure
in patients with mild to moderate13 and mild to se-
vere hypertension.14 Rurgress et al.13 evaluated
eplerenone's ability to achieve a diastolic blood
pressure (DBP) <90 mmHg or a systolic blood
pressure (SBP) <140 mmHg when titrated from 50
mg/day up to 200 mg/day and found that the dose
response relationship began to plateau at 100 mg. If
blood pressure remained uncontrolled at anytime
from week 6 to the end of month 3, a second medi-
cation was added. The mean changes in SBP/DBP
from baseline for the different eplerenone doses are
summarized in Table 1. A total of 433 patients
(74.3%) were classified as responders, that is, pa-
tients with a DBP <90 mmHg or a >10 mmHg
change from baseline. In addition, 261 of the re-
sponders (44.8%) had responded to eplerenone
monotherapy. White et al.14 found eplerenone 100
mg once daily to be the maximum effective dose in
patients with mild to severe hypertension. The re-
sults of this study are also summarized in Table 1.

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Table 2. Mean Blood Pressure Change from Baseline to 16 weeks 15
EPL LOS PBO p-value
All patients
A SBP/DBP (mm Hg) -12.8/-10.3 -6.3/-6.9 -3.4/-5.3 <0.001/<0.001 <0.001/<0.001
African American patients
A SBP/DBP (mmHg) -13.5/-10.2 -5.3/-6.0 -3.7/-4.8 <0.001/<0.001 <0.001/<0.001
White patients
A SBP/DBP (mmHg) -12.3/-11.1 -8.5/-8.4 -3.2/-6.4 <0.001/0.001 <0.126/<0.068
EPL eplerenone, LOS losartan, PBO placebo

Eplerenone vs. Spironolactone
Eplerenone's effect on blood pressure was
evaluated in a double-blinded, placebo controlled
trial.24 Various doses of eplerenone were compared
to a fixed dose of spironolactone. The study was an
8-week, multi-center, double-blinded, placebo-
controlled trial designed to assess the efficacy,
safety, and tolerability of eplerenone. Eligible pa-
tients were randomized to eplerenone 50, 100, 200,
or 400 mg once daily; eplerenone 25, 50, or 200 mg
twice daily; spironolactone 50 mg twice daily; or
placebo. Four hundred and nine out of 417 random-
ized patients were evaluated for efficacy. The ad-
justed mean change from baseline to final visit in
sitting and standing SBP and DBP was significantly
greater (p < 0.05) in all eplerenone groups com-
pared to the placebo group. The adjusted mean
change in 24-h ambulatory blood pressure monitor-
ing (ABPM) measurements of SBP and DBP were
significantly greater (p < 0.05) in eplerenone-
treated patients than placebo. Significant reductions
(p < 0.01) in SBP and DPB compared to placebo
were also observed in the spironolactone group.
Adjusted mean changes from baseline to final visit
in SBP and DBP for eplerenone 100 mg daily and
50 mg twice daily were approximately 50% to 75%
of those observed in the twice daily 50 mg spiro-
nolactone group. The incidence of adverse events
was similar to placebo with the exception of in-
creased levels of serum potassium observed in both
eplerenone-treated and spironolactone-treated pa-
tients. No antiandrogenic or progestational effects
or clinically relevant safety issues were observed in
eplerenone-treated patients. However, one spiro-
nolactone-treated patient reported menstrual irregu-

Eplerenone vs. Losartan
Pratt15 evaluated eplerenone's ability to
lower blood pressure compared to the ARB losartan
and placebo. The primary outcome of the study was
change from baseline in trough DBP after 16 weeks
of therapy. Following a 4-week period, 551 un-
treated hypertensive patients were randomized to
receive either eplerenone 50 mg/d, losartan 50
mg/d, or placebo. After 16 weeks of treatment, the
mean change in DBP was 10.3 mmHg for
eplerenone, 6.9 mmHg for losartan, and 5.3 mmHg
for placebo (Table 2). The study also evaluated the
treatment effects according to race. African Ameri-
can patients demonstrated a greater mean change in
DBP compared to losartan (p<0.001) or placebo
(p<0.001). However, eplerenone's effect on blood
pressure in white patients was similar to that of
losartan but significantly better than placebo. Based
on this study, eplerenone appears to be more effec-
tive than losartan for the treatment of hypertension
in African American patients.

Eplerenone vs. Enalapril
Burgess and colleagues27 compared
eplerenone to the ACE inhibitor enalapril in pa-
tients with mild to moderate hypertension (95
mmHg < DBP <110 mmHg). Patients were ran-
domized to receive eplerenone 50 mg daily
(N=253) or enalapril 10 mg daily (N=246) initially.
If DBP was >90 mmHg at week 4, 8, 12, 16, or 20,
the doses were increased to 100 mg and 200 mg
daily for eplerenone or 20 mg and 40 mg daily for
enalapril. Blood Pressure (SBP/DBP) was compa-
rably reduced by both drugs at week 24 (eplerenone
-14.5/-11.2 mmHg, enalapril -12.7/-11.3 mmHg)
and 12 months (eplerenone -16.5/-13.3 mmHg,
enalapril -14.8/-14.1 mmHg). However, patients

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Table 3. Rate (%) of adverse events occurring in > 1% of
patients treated with eplerenone (25 mg to 400 mg) 11,31

Eplerenone Placebo
(N=945) (N=372)
Hypercholesterolemia 1% 0%
Hyperglycemia 1% 0%
Hyperkalemia 2.7% 1.3%
Diarrhea 2% 1%
Abdominal pain 1% 0%
Albuminuria 1% 0%
Cough 2% 1%
Central Nervous System
Dizziness 3% 2%
Fatigue 2% 1%
Influenza like symptoms 2% 1%

receiving enalapril had a significantly higher inci-
dence of adverse effects, including cough (6.5% vs.
2.4 %, P= 0.029) and hyperglycemia (2.8% vs.
0.4%, P = 0.035). No data on the incidence of hy-
perkalemia was reported.

Combination therapy trials
Eplerenone's efficacy was evaluated as an
adjunctive agent with other antihypertensive agents
in several clinical trials. Krum et al examined
eplerenone's effect on blood pressure when added
to a treatment regimen containing either an ACE
inhibitor or ARB. Patients were randomized to re-
ceive eplerenone 50 mg/d or placebo in addition to
the fixed-dose ACE inhibitor or ARB. After 2, 4, or
6 weeks of treatment, the dose of eplerenone or
matching placebo was doubled if DBP was >90
mmHg (maximum dose 100 mg/d). Following 8
weeks of treatment, patients taking an ACE inhibi-
tor who received eplerenone had a significantly
greater decrease from baseline in mean SBP than
patients who received placebo (13.4 vs. 7.5 mmHg;
p=0.002). After adding eplerenone, patients taking
an ARB also showed significant decreases from
baseline in both SBP and DBP compared to pla-
cebo (SBP 16.0 vs. 9.2 mmHg, p=0.001; DBP 12.7
vs. 9.3 mmHg; p=0.004). These comparison studies

demonstrated that blood pressure can be further de-
creased when eplerenone is added to either an ACE
inhibitor or ARB.
Pitt et al.26 investigated eplerenone's effi-
cacy in patients with mild to moderate hypertension
and left ventricular hypertrophy. One hundred and
fifty three patients were assigned to eplerenone 200
mg/d, enalapril 40 mg/d, or the combination of
eplerenone 200 mg and enalapril 10 mg/d. The in-
vestigator titrated the doses over 4 weeks. If at
week 8 BP remained uncontrolled (DBP >90
mmHg or SBP >180 mmHg) with the full daily
dose, hydrochlorothiazide 12.5 mg and 25 mg, or
amlodipine 10 mg was added. The primary end
point was change from baseline in left-ventricular
mass (LVM). Secondary endpoints included blood
pressure control, change in microalbuminuria, and
treatment safety and tolerability. There was a sig-
nificant reduction in LVM in the combination and
eplerenone groups (p=0.007), but not for the enala-
pril group (p=0.107). Both SBP and DBP were sig-
nificantly reduced from baseline in both groups.
SBP decreased by 23.8 mmHg in the eplerenone
group, 24.7 mmHg in the enalapril group (p=0.718
for the between-group comparison), and 28.7
mmHg in the combination group (p=0.048 for
eplerenone vs. combination; p=0.098 for enalapril
vs. combination). Finally, the percent change from
baseline in microalbuminuria was significantly re-
duced among the 3 groups. Interestingly, they
found that the combination produced significant re-
ductions when compared with either agent alone
(p=0.001 vs. eplerenone; p=0.038 vs. enalapril).
Based on these data, it appears that eplerenone can
lower blood pressure, reduce LVM, and decrease
microalbuminuria similar to enalapril.

Heart Failure
The Eplerenone Neurohormonal Efficacy
and Survival Trial (EPHESUS)19'28 is an ongoing
study that will evaluate eplerenone in the treatment
of heart failure. Approximately 6200 patients will
receive eplerenone 25-50 mg/d or placebo and will
be followed for a total of 2.5 years. The rationale
for this study was based on the results from the
Randomized Aldactone Evaluation Study (RALES)
in patients with chronic stable heart failure.30 The
primary endpoints are rate of all-cause mortality
and combined rate of cardiovascular mortality or
morbidity due to hospitalization. Additional end-

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Table 4. Changes in serum potassium with eplerenoneut
Mean change % > 5.5
Dose N (mEq/d) (mEq/L)

Placebo 194 0 1
25 97 0.08 0
50 245 0.14 0
100 193 0.09 1

points include hospitalizations, functional class,
quality of life, new-onset atrial fibrillation/flutter,
and economic evaluations. Subgroup analysis will
examine eplerenone's effect on cardiac remodeling,
collagen metabolism, vascular compliance, heart
rate variability, thrombolytic balance, and proteinu-
ria. The results from this trial will provide health
care professionals with important data regarding
the use of eplerenone as part of the heart failure
treatment regimen, as well as, data concerning the
effects of aldosterone receptor blockade following
acute myocardial infarction.

Dosing and Administration
Eplerenone doses ranging from 25 mg to
400 mg/day in one or two divided doses have been
evaluated in clinical hypertension trials. The dose
response curve appears to plateau at 100 mg/day.
Based on this data, the recommended starting dose
of eplerenone is 50 mg administered once daily.
The full therapeutic effect of eplerenone is appar-
ent within 4 weeks. For patients with an inadequate
blood pressure response at 50 mg once daily, the
dosage should be increased to 50 mg twice daily.
Eplerenone may be used alone or in combination
with other antihypertensive agents. Higher dosages
of eplerenone are not recommended because they
have no greater effect on blood pressure or because
they are associated with an increased risk of hyper-

Toxicity and Safety
Complete data on adverse events for
eplerenone has not been published. Based on the
available information from clinical trials, the inci-
dence of adverse events from eplerenone (25 mg to
400 mg) is similar to that of placebo. One of the
most common adverse effects seen in clinical trials
for hypertension was hyperkalemia, with a reported

incidence of 2.7% compared to 1.3% for placebo.31
In the combined losartan and add-on hypertension
trials,24 of the 269 patients treated with eplerenone,
only 1% experienced hyperkalemia or hyperurice-
mia. There was a clinically significant higher inci-
dence of hyperkalemia (defined as K' >6.0 mEq/L)
among heart failure patients receiving eplerenone
100 mg/d (12.0%) compared to spironolactone 25
mg/d (8.7%). However, most of the patients in this
study also received concurrent ACE inhibitor ther-
apy.23 The most common reasons for discontinua-
tion were headache, dizziness, and increased serum
gamma glutamyl transpeptidase (GGT).11 Less than
1% of patients reported impotence or menstrual ab-
normalities. These results are summarized in Table
3 and 4.

Eplerenone is not marketed yet. Therefore,
price information is not available at this time.

Eplerenone is a novel agent that selectively
blocks aldosterone. It is indicated for the treatment
of hypertension alone or in combination with other
antihypertensive agents. Eplerenone appears be
more beneficial than other non-selective aldoster-
one blockers, such as spironolactone, due to it's
limited progestational and antiandrogenic side ef-
fects. It is also being investigated for its potential
use in heart failure patients. However, much of this
data has only appeared in review and abstract form.
Until additional research on the clinical use of
eplerenone in heart failure patients and results from
the ongoing EPHESUS trial are published,
eplerenone's role in heart failure patients will re-
main uncertain.

1. The Sixth report of the Joint National Committee on Pre-
vention. Detection, Evaluation, and Treatment of High
Blood Pressure. Arch Intern Med. 1997; 157: 2413-43.
2. American Heart Association. 2002 Heart and Stroke Sta-
tistical Update. Dallas, TX,.
3. Dipiro JT et al. Pharmacotherapy: A Pathophysiological
Approach, 4th ed.; Appleton and Lange; 1999.
4. Weber WT. Aldosterone in congestive heart failure. N
Engl J Med 2001; 345:1689-97.
5. Struthers AD. Aldosterone escape during angiotensin-
converting enzyme inhibitor therapy in chronic heart fail-
ure. J Card Fail 1996; 2:47-54.
6. Laragh J. Laragh's lessons in pathophysiology and clini-

PharmaNote Volume 18, Issue 6 March 2003


Volume 18, Issue 6 March 2003

cal pearls for treating hypertension. Am J Hypertens
2001; 14:186-94.
7. Hameedi A, C ludoll HL. The promise of selective aldos-
terone receptor antagonists for the treatment of hyperten-
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8. Quaschning T, et al. Aldosterone receptor antagonism
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9. McKelvie RS et al. Comparison of candesartan, enalapril,
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10. Jeunmaitre X, et al. Efficacy and tolerance of spironolac-
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12. Martin J, Krum H. Eplerenone (GD Searle & Co.). Curr
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13. Rurgess E, et al. The selective aldosterone blocker
eplerenone is safe and efficacious for the long term treat-
ment of mild to moderate hypertension. Am J Hypertens
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14. White WB, et al. Assessment of the novel selective al-
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15. Pratt JH, et al. Efficacy and tolerability of eplerenone and
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advanced left ventricular dysfunction. J Am Coll Cardiol
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evolution of utility and pharmacology. Kidney Int
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one receptor antagonist (SARA): dose finding study in
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